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Transferrin Receptor-Mediated Iron Uptake Promotes Colon Tumorigenesis
Advanced Science ( IF 14.3 ) Pub Date : 2023-01-26 , DOI: 10.1002/advs.202207693 Hyeoncheol Kim 1 , Luke B Villareal 1 , Zhaoli Liu 1 , Mohammad Haneef 1 , Daniel M Falcon 1 , David R Martin 2 , Ho-Joon Lee 3 , Michael K Dame 4 , Durga Attili 5 , Ying Chen 6 , James Varani 5 , Jason R Spence 4 , Olga Kovbasnjuk 7 , Justin A Colacino 8 , Costas A Lyssiotis 3 , Henry C Lin 9 , Yatrik M Shah 3 , Xiang Xue 1
Advanced Science ( IF 14.3 ) Pub Date : 2023-01-26 , DOI: 10.1002/advs.202207693 Hyeoncheol Kim 1 , Luke B Villareal 1 , Zhaoli Liu 1 , Mohammad Haneef 1 , Daniel M Falcon 1 , David R Martin 2 , Ho-Joon Lee 3 , Michael K Dame 4 , Durga Attili 5 , Ying Chen 6 , James Varani 5 , Jason R Spence 4 , Olga Kovbasnjuk 7 , Justin A Colacino 8 , Costas A Lyssiotis 3 , Henry C Lin 9 , Yatrik M Shah 3 , Xiang Xue 1
Affiliation
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Transferrin receptor (TFRC) is the major mediator for iron entry into a cell. Under excessive iron conditions, TFRC is expected to be reduced to lower iron uptake and toxicity. However, the mechanism whereby TFRC expression is maintained at high levels in iron-enriched cancer cells and the contribution of TFRC to cancer development are enigmatic. Here the work shows TFRC is induced by adenomatous polyposis coli (APC) gene loss-driven β-catenin activation in colorectal cancer, whereas TFRC-mediated intratumoral iron accumulation potentiates β-catenin signaling by directly enhancing the activity of tankyrase. Disruption of TFRC leads to a reduction of colonic iron levels and iron-dependent tankyrase activity, which caused stabilization of axis inhibition protein 2 (AXIN2) and subsequent repression of the β-catenin/c-Myc/E2F Transcription Factor 1/DNA polymerase delta1 (POLD1) axis. POLD1 knockdown, iron chelation, and TFRC disruption increase DNA replication stress, DNA damage response, apoptosis, and reduce colon tumor growth. Importantly, a combination of iron chelators and DNA damaging agents increases DNA damage response and reduces colon tumor cell growth. TFRC-mediated iron import is at the center of a novel feed-forward loop that facilitates colonic epithelial cell survival. This discovery may provide novel strategies for colorectal cancer therapy.
中文翻译：
转铁蛋白受体介导的铁摄取促进结肠肿瘤发生
转铁蛋白受体 (TFRC) 是铁进入细胞的主要介质。在铁过量的情况下，TFRC 预计会减少，以降低铁的吸收和毒性。然而，富铁癌细胞中 TFRC 表达维持高水平的机制以及 TFRC 对癌症发展的贡献仍然是个谜。这项研究表明，结直肠癌中，TFRC 是由腺瘤性结肠息肉病 (APC) 基因缺失驱动的β-连环蛋白激活诱导的，而 TFRC 介导的瘤内铁积累则增强了β-连环蛋白的激活。-连环蛋白信号传导通过直接增强坦科聚合酶的活性。TFRC 的破坏导致结肠铁水平和铁依赖性端锚聚合酶活性降低，从而导致轴抑制蛋白 2 (AXIN2) 稳定并随后抑制β-catenin/c-Myc/E2F 转录因子 1/DNA 聚合酶 delta1 (POLD1) 轴。POLD1 敲低、铁螯合和 TFRC 破坏会增加 DNA 复制应激、DNA 损伤反应、细胞凋亡，并减少结肠肿瘤生长。重要的是，铁螯合剂和 DNA 损伤剂的组合可以增强 DNA 损伤反应并减少结肠肿瘤细胞的生长。TFRC 介导的铁输入是促进结肠上皮细胞存活的新型前馈循环的中心。这一发现可能为结直肠癌的治疗提供新策略。
更新日期：2023-01-26
中文翻译：
转铁蛋白受体介导的铁摄取促进结肠肿瘤发生
转铁蛋白受体 (TFRC) 是铁进入细胞的主要介质。在铁过量的情况下，TFRC 预计会减少，以降低铁的吸收和毒性。然而，富铁癌细胞中 TFRC 表达维持高水平的机制以及 TFRC 对癌症发展的贡献仍然是个谜。这项研究表明，结直肠癌中，TFRC 是由腺瘤性结肠息肉病 (APC) 基因缺失驱动的β-连环蛋白激活诱导的，而 TFRC 介导的瘤内铁积累则增强了β-连环蛋白的激活。-连环蛋白信号传导通过直接增强坦科聚合酶的活性。TFRC 的破坏导致结肠铁水平和铁依赖性端锚聚合酶活性降低，从而导致轴抑制蛋白 2 (AXIN2) 稳定并随后抑制β-catenin/c-Myc/E2F 转录因子 1/DNA 聚合酶 delta1 (POLD1) 轴。POLD1 敲低、铁螯合和 TFRC 破坏会增加 DNA 复制应激、DNA 损伤反应、细胞凋亡，并减少结肠肿瘤生长。重要的是，铁螯合剂和 DNA 损伤剂的组合可以增强 DNA 损伤反应并减少结肠肿瘤细胞的生长。TFRC 介导的铁输入是促进结肠上皮细胞存活的新型前馈循环的中心。这一发现可能为结直肠癌的治疗提供新策略。
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